The overall goal of this research program is to understand the role of the c-Jun N-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases. Many of the components of the JNK protein kinase cascade have been identified by molecular cloning and have been characterized in biochemical studies. However, an understanding of the physiological role of the JNK signaling pathway has remained elusive. The long-term goal of this research is to define function of the JNK signaling pathway in the beta cell. Previous studies have demonstrated that JNK can phosphorylate and inhibit the function of insulin receptor substrate (IRS) proteins. In addition, the JIP scaffold proteins that co-ordinate the JNK protein kinase cascade have been found to be mutated in diabetic humans. We have constructed several mouse models with defects in the JNK signaling pathway, including mice with defects in the JIP scaffold proteins. These mouse models will be used to study the function of these proteins in beta cells Achievement of the goals of this proposal will increase understanding of signal transduction; mechanisms that contribute to normal beta cell function. This information may represent a basis for the design of novel therapeutic strategies for the treatment of diabetes. The Specific Aims of this proposal are to employ mouse models to: Define the role of JNK in beta cells. Define the role of JIP scaffold proteins in beta cells Define the function of diabetes-associated mutations in JIP1